Kenneth Es Poole

Changing structure of the femoral neck across the adult female lifespan.

The anatomic distribution of cortical and cancellous bone in the femoral neck may be critical in determining resistance to fracture. We investigated the effects of aging on femoral neck bone in women. In this cross‐sectional study, we used clinical multidetector computed tomography (MDCT) of the hips to investigate aging effects in 100 female volunteers aged 20 to 90 years. We developed a clinically efficient protocol to measure cortical thickness (C.Th) and cortical, trabecular, and integral bone mineral density (CtBMD, TrBMD, and iBMD in mg/cm3) in anatomic quadrants of the femoral neck. We used a nested ANOVA to evaluate their associations with height, weight, location in the femoral neck, and age of the subject. Age was the principal determinant of both cortical thickness and BMD. Age had significantly different effects within the anatomic quadrants; compared with young women, elderly subjects had relative preservation of the inferoanterior (IA) quadrant but strikingly reduced C.Th and BMD superiorly. A model including height, weight, and region of interest (and their interactions) explained 83% of the measurement variance (pu2009<u2009.0001). There were marked C.Th and BMD differences between age 25 and age 85 in the already thin superior quadrants. At 25 years the predicted C.Th of the superoposterior quadrant was 1.63u2009mm, whereas at 85 years it was 0.33u2009mm [−1.33u2009mm, 95% confidence interval (CI) of difference over 60 years −1.69 to −0.95]. By contrast, at 25 years mean C.Th of the IA quadrant was 3.9u2009mm, whereas at 85 years it was 3.3u2009mm (−0.6u2009mm, 95% CI −0.83 to −0.10). CtBMD of the IA region was equivalent at 25 and 85 years. In conclusion, elderly women had relative preservation of IA femoral neck bone over seven decades compared with young women but markedly lower C.Th and BMD in the other three quadrants. The IA quadrant transmits mechanical load from walking. Mechanical theory and laboratory tests on cadaveric femurs suggest that localized bone loss may increase the risk of fracture in elderly fallers. It remains to be determined whether this MDCT technique can provide better prediction of hip fracture than conventional clinical dual X‐ray absorptiometry (DXA).

Sclerostin and the regulation of bone formation: Effects in hip osteoarthritis and femoral neck fracture

Remodeling imbalance in the elderly femoral neck can result in thin cortices and porosity predisposing to hip fracture. Hip osteoarthritis protects against intracapsular hip fracture. By secreting sclerostin, osteocytes may inhibit Wnt signaling and reduce bone formation by osteoblasts. We hypothesised that differences in osteocytic sclerostin expression might account for differences in osteonal bone‐formation activity between controls and subjects with hip fracture or hip osteoarthritis. Using specific antibody staining, we determined the osteocytic expression of sclerostin within osteons of the femoral neck cortex in bone removed from subjects undergoing surgery for hip osteoarthritis (hOA: 5 males, 5 females, 49 to 92 years of age) or hip fracture fixation (FNF: 5 males, 5 females, 73 to 87 years of age) and controls (C: 5 males, 6 females, 61 to 90 years of age). Sclerostin expression and distances of each osteocyte to the canal surface and cement line were assessed for all osteonal osteocytes in 636 unremodeled osteons chosen from fields (∼0.5u2009mm in diameter) with at least one canal staining for alkaline phosphatase (ALP), a marker of bone formation. In adjacent sections, ALP staining was used to classify basic multicellular unit (BMUs) as quiescent or actively forming bone (ALP+). The areal densities of scl− and scl+ osteocytes (number of cells per unit area) in the BMU were inversely correlated and were strong determinants of ALP status in the BMU. In controls and hip fracture patients only, sclerostin‐negative osteocytes were closer to osteonal surfaces than positively stained cells. Osteon maturity (progress to closure) was strongly associated with the proportion of osteonal osteocytes expressing sclerostin, and sclerostin expression was the chief determinant of ALP status. hOA patients had 18% fewer osteocytes per unit bone area than controls, fewer osteocytes expressed sclerostin on average than in controls, but wide variation was seen between subjects. Thus, in most hOA patients, there was increased osteonal ALP staining and reduced sclerostin staining of osteocytes. In FNF patients, newly forming osteons were similar in this respect to hOA osteons, but with closure, there was a much sharper reduction in ALP staining that was only partly accounted for by the increased proportions of osteonal osteocytes staining positive for sclerostin. There was no evidence for a greater effect on ALP expression by osteocytes near the osteonal canal. In line with data from blocking antibody experiments, osteonal sclerostin appears to be a strong determinant of whether osteoblasts actively produce bone. In hOA, reduced sclerostin expression likely mediates increased osteoblastic activity in the intracapsular cortex. In FNF, full osteonal closure is postponed, with increased porosity, in part because the proportion of osteocytes expressing sclerostin increases sharply with osteonal maturation.

Predicting hip fracture type with cortical bone mapping (CBM) in the Osteoporotic Fractures in Men (MrOS) study

Hip fracture risk is known to be related to material properties of the proximal femur, but fracture prediction studies adding richer quantitative computed tomography (QCT) measures to dual‐energy X‐ray (DXA)‐based methods have shown limited improvement. Fracture types have distinct relationships to predictors, but few studies have subdivided fracture into types, because this necessitates regional measurements and more fracture cases. This work makes use of cortical bone mapping (CBM) to accurately assess, with no prior anatomical presumptions, the distribution of properties related to fracture type. CBM uses QCT data to measure the cortical and trabecular properties, accurate even for thin cortices below the imaging resolution. The Osteoporotic Fractures in Men (MrOS) study is a predictive case‐cohort study of men over 65 years old: we analyze 99 fracture cases (44 trochanteric and 55 femoral neck) compared to a cohort of 308, randomly selected from 5994. To our knowledge, this is the largest QCT‐based predictive hip fracture study to date, and the first to incorporate CBM analysis into fracture prediction. We show that both cortical mass surface density and endocortical trabecular BMD are significantly different in fracture cases versus cohort, in regions appropriate to fracture type. We incorporate these regions into predictive models using Cox proportional hazards regression to estimate hazard ratios, and logistic regression to estimate area under the receiver operating characteristic curve (AUC). Adding CBM to DXA‐based BMD leads to a small but significant (pu2009<u20090.005) improvement in model prediction for any fracture, with AUC increasing from 0.78 to 0.79, assessed using leave‐one‐out cross‐validation. For specific fracture types, the improvement is more significant (pu2009<u20090.0001), with AUC increasing from 0.71 to 0.77 for trochanteric fractures and 0.76 to 0.82 for femoral neck fractures. In contrast, adding DXA‐based BMD to a CBM‐based predictive model does not result in any significant improvement.

Response to: Comment on: "Denosumab Rapidly Increases Cortical Bone in Key Locations of the Femur: A 3D Bone Mapping Study in Women With Osteoporosis".

Kenneth ES Poole, Graham M Treece, Andrew H Gee, Jacques P Brown, Michael R McClung, Andrea Wang, and Cesar Libanati Department of Medicine, University of Cambridge, Cambridge, UK Department of Engineering, University of Cambridge, Cambridge, UK CHU de Qu ebec Research Centre (CRCHU), Laval University, Quebec City, Qu ebec, Canada Oregon Osteoporosis Center, Portland, OR, USA Amgen Inc., Thousand Oaks, CA, USA